1. Field
The present disclosure relates generally to piperazinylpyrimidine analogs and uses thereof. The invention also relates to methods of preparing these compounds.
2. Related Art
The human kinome, represented by 518 kinases, is a widely investigated protein family on biological, chemical, and clinical levels. Protein kinases are involved in the majority of signal transduction pathways regulating the cell machinery of survival, proliferation, and maintenance. Accordingly, several pathological abnormalities are correlated with aberrations in the operational integrity and accuracy of certain kinases inside the cell, making kinases attractive targets for treating, diagnosing, and establishing personalized therapies of various disorders such as different malignancies, neurodegenerative disorders, rheumatoid arthritis, autoimmune diseases, and others (Eglen, R. M.; Reisine, T. Assay and Drug Development Technologies 2009, 7, 22-43; Eglen, R. M.; Reisine, T. Expert Opinion on Drug Discovery 2010, 5, 277-290; Parikh, K.; Peppelenbosch, M. P. Cancer Research 2010, 70, 2575-2578; McDermott, U.; Settleman, J. Journal of Clinical Oncology 2009, 27, 5650-5659).
Kinase inhibitors, either small molecules or monoclonal antibodies, represent a class of molecularly targeted anticancer agents; approximately 14 kinase targeting agents have earned FDA approval during the last two decades as either anticancer or antiangiogenic agents. In comparison, not as many agents targeting other cancer-relevant families such as Bcl-2 proteins, histone deacetylases, and phosphatases, have gained regulatory approval. Furthermore, the discovery, preclinical, and clinical development of novel kinase inhibitors currently are the focus of pharmaceutical industry research efforts, especially those seeking novel and effective cancer controlling agents (Selzer, E. Expert Review of Clinical Pharmacology 2010, 3, 161-163).
The design of selective kinase inhibitors has proven to be challenging due to the conservation of the ATP binding site, targeted by most inhibitors, among different kinases. Several design strategies, both computer assisted, bioinformatics aided, and structure based, have been implemented to tailor more selective kinase inhibitors against a subset of kinases or certain kinase subfamilies (Eglen, R. M.; Reisine, T. Expert Opinion on Drug Discovery 2010, 5, 277-290; Akritopoulou-Zanze, I.; Hajduk, P. J. Drug Discovery Today 2009, 14, 291-297; Bogoyevitch, M. A.; Fairlie, D. P. Drug Discovery Today 2007, 12, 622-633; Huang, D. et al. Bioinformatics 2009, 26, 198-204; Kirkland, L. O.; McInnes, C. Biochemical Pharmacology 2009, 77, 1561-1571; Smyth, L. A.; Collins, I. Journal of Chemical Biology 2009, 2, 131-151; Aronov, A. M. et al. Journal of Medicinal Chemistry 2008, 51, 1214-1222; Knight, Z. A.; Shokat, K. M. Chemistry and Biology 2005, 12, 621-637). One successful example is lapatinib, which is known to be a selective inhibitor against many wild-type and mutant EGFR subfamily members and is currently utilized clinically in combination with capecitabine for metastatic breast cancer. In contrast, sunitinib, another successfully marketed kinase inhibitor, has been shown in several studies to be a highly promiscuous agent capable of interacting with more than 15% of kinases with a very high affinity (Kd<100 nM) (Morphy, R. Journal of Medicinal Chemistry 2010, 53, 1413-1437; Karaman, M. W. et al. Nature Biotechnology 2008, 26, 127-132). The selectivity of lapatinib compared to the promiscuity of sunitinib is usually rationalized by the observation that lapatinib is a type-II inhibitor which binds to the ATP-binding site as well as penetrating the adjacent allosteric binding site of its target kinases, whereas sunitinib is a type-I inhibitor that binds mainly to the ATP-binding site of several kinases (Gajiwaia, K. S. Proceedings of the National Academy of Sciences of the United States of America 2009, 106, 1542-1547; Wood, E. R. et al. Cancer Research 2004, 64, 6652-6659). However, it is unjustified, according to several published reports, to claim that every type-I kinase inhibitor is promiscuous and that every type-II inhibitor is selective (Karaman, M. W. et al. Nature Biotechnology 2008, 26, 127-132). Additionally, a given small molecule kinase inhibitor usually tends to recognize a given conformational ensemble of its target kinase(s) that may happen to differentially belong to either the active and/or the inactive state. That is to say that a type-I inhibitor, for example, may still bind to the inactive form of its kinase but with less affinity than with the active state. Considering another dimension of variability, some inhibitors interact potently with both the active and the inactive forms of their targeted kinases. For example, MK-2461 is able to bind with considerable potency to both the phosphorylated and the unphosphorylated forms of c-MET kinase with a measured binding constant (Kd) of 4.4 and 27.2 nM respectively (Pan, B. S. et al. Cancer Research 2010, 70, 1524-1533). Contrary to the behavior of MK-2461, sunitinib exhibits a strong differential selectivity towards the unactivated wild-type KIT versus the active form (Gajiwaia, K. S. et al. Proceedings of the National Academy of Sciences of the United States of America 2009, 106, 1542-1547). Generally speaking, the clinical fact that both lapatinib and sunitinib have successfully helped save or at least improve the life quality of certain cancer patient populations illustrates that, when it comes to kinase inhibitors, it is arguable that selectivity is always a virtue and non-selectivity is a constant drawback. In fact, some kinase modulating agents may achieve better clinical outcomes via targeting several kinases whereas others can cause troublesome side effects even while being selective (Petrelli, A.; Giordano, S. Current Medicinal Chemistry 2008, 15, 422-432). Moreover, small molecules generally and kinase inhibitors specifically are usually promiscuous hitters of several protein families and that could be why not all potent kinase inhibitors survive through the drug development process (McGovern, S. L.; Shoichet, B. K. Journal of Medicinal Chemistry 2003, 46, 1478-1483).
The phenomenon of kinase inhibitors being mostly non-selective has inspired the founding of several high-throughput kinase profiling screens in order to determine intended as well as off-target kinases affected by a given kinase inhibitor (Karaman, M. W. et al. Nature Biotechnology 2008, 26, 127-132; Fedorov, O. et al. Proceedings of the National Academy of Sciences of the United States of America 2007, 104, 20523-20528; Ma, H. et al. Expert Opinion on Drug Discovery 2008, 3, 607-621). These screens have been used to investigate the kinase binding potential or the functional inhibitory activity of a given small molecule against a large panel of kinases and thereby have facilitated uncovering some of the structural features relevant to promiscuity. However, it is now appreciated that a given kinase may be more promiscuous than another even with a difference of only a few amino acids because the conformational space of the kinase depends on structural features at the primary, secondary, and tertiary levels (Bamborough, P. et al. Journal of Medicinal Chemistry 2008, 51, 7898-7914). A deeper understanding of protein kinase promiscuity in cases where there are correlations between the ATP-binding sites of certain subfamilies that are not closely related based on sequence similarity is needed (Kinnings, S. L.; Jackson, R. M. Journal of Chemical Information and Modeling 2009, 49, 318-329). Resistance through several mechanisms, most frequently single point mutation, has been developed by cancer cells towards several kinase inhibitors; those who target proliferation and/or angiogenesis including both selective and non-selective kinase inhibitors (Christoffersen, T. et al. European Journal of Pharmacology 2009, 625, 6-22; Martin, A. P. et al. Cancer Biology and Therapy 2010, 8, 2084-2096; Pages, G.; Grepin, R. Journal of Oncology 2010).
Thus, there remains a need for novel protein kinase inhibitor compounds with desirable pharmaceutical properties.